Interventional Cardiology
Adenosine diphosphate–induced platelet-fibrin clot
strength: A new thrombelastographic indicator of
long-term poststenting ischemic events
Paul A. Gurbel, MD, a Kevin P. Bliden, BS, a Irene A. Navickas, BS, b Elizabeth Mahla, MD, a Joseph Dichiara, BS, a
Thomas A. Suarez, MD, a Mark J. Antonino, BS, a Udaya S. Tantry, PhD, a and Eli Cohen, PhD b
Baltimore, MD; and Niles, IL
Background
Poststenting ischemic events occur despite dual-antiplatelet therapy, suggesting that a “one size fits all”
antithrombotic strategy has significant limitations. Ex vivo platelet function measurements may facilitate risk stratification and
personalized antiplatelet therapy.
Methods We investigated the prognostic utility of the strength of adenosine diphosphate (ADP)–induced (MAADP) and
thrombin-induced (MATHROMBIN) platelet-fibrin clots measured by thrombelastography and ADP-induced light transmittance
aggregation (LTAADP) in 225 serial patients after elective stenting treated with aspirin and clopidogrel. Ischemic and bleeding
events were assessed over 3 years.
Results Overall, 59 (26%) first ischemic events occurred. Patients with ischemic events had higher MAADP, MATHROMBIN,
and LTAADP (P b .0001 for all comparisons). By receiver operating characteristic curve analysis, MAADP N47 mm had the best
predictive value of long-term ischemic events compared with other measurements (P b .0001), with an area under the curve =
0.84 (95% CI 0.78-0.89, P b .0001). The univariate Cox proportional hazards model identified MAADP N47 mm,
MATHROMBIN N69 mm, and LTAADP N34% as significant independent predictors of first ischemic events at the 3-year time point,
with hazard ratios of 10.3 (P b .0001), 3.8 (P b .0001), and 4.8 (P b .0001), respectively. Fifteen bleeding events occurred.
Receiver operating characteristic curve and quartile analysis suggests MAADP ≤31 as a predictive value for bleeding.
Conclusion This study is the first demonstration of the prognostic utility of MAADP in predicting long-term event occurrence
after stenting. The quantitative assessment of ADP-stimulated platelet-fibrin clot strength measured by thrombelastography can
serve as a future tool in investigations of personalized antiplatelet treatment designed to reduce ischemic events and bleeding.
(Am Heart J 2010;160:346-54.)
Ischemic events after percutaneous coronary intervention (PCI) are influenced by platelet activation and
thrombin generation.1,2 Antiplatelet therapy with clopidogrel and aspirin is the current standard of care for
patients undergoing PCI. Despite the proven benefits of
adding clopidogrel to aspirin therapy, a significant
percentage of patients will experience both short- and
long-term poststenting ischemic events, suggesting that
the current “one size fits all” dosing strategy has
significant limitations.3
From the aSinai Center for Thrombosis Research, Baltimore, MD, and bHaemoscope
Corporation, Niles, IL.
Submitted December 15, 2009; accepted May 5, 2010.
Reprint requests: Paul A. Gurbel, MD, Sinai Center for Thrombosis Research, Shapiro
Building, Suite 209, 2401 W Belvedere Ave, Baltimore, MD 21215.
E-mail: [email protected]
0002-8703/$ - see front matter
© 2010, Mosby, Inc. All rights reserved.
doi:10.1016/j.ahj.2010.05.034
The existing treatment paradigm of dual-antiplatelet
therapy is based on the results of prospective, randomized large-scale clinical trials that did not include
concomitant assessments of platelet function.3 Currently,
uniform dosing and duration of antiplatelet treatment are
recommended irrespective of the individual patient's
response to antiplatelet therapy. The latter approach is
based on the inherent assumption that all poststenting
patients have the same level of antiplatelet response and
hemostasis. The limitations of the latter approach have
been revealed by demonstration of wide variability in
clopidogrel responsiveness in multiple pharmacodynamic studies.4 At one end of the spectrum, selected patients
with excessively low on-treatment platelet reactivity may
have unnecessary bleeding, whereas patients with high
platelet reactivity may experience ischemic events.
Subsequently, an increasing body of translational research data has demonstrated a strong relation of high
on-treatment platelet reactivity primarily measured by
American Heart Journal
Volume 160, Number 2
conventional light transmittance aggregometry after
stimulation by adenosine diphosphate (LTAADP) to poststenting ischemic event occurrence.4
A previous report demonstrated that high thrombininduced platelet-fibrin clot strength (MATHROMBIN) measured by thrombelastography (TEG) and high LTAADP
were risk factors for 6-month post-PCI ischemic events. In
that study, MATHROMBIN was a better risk discriminator.5
Herein, we report the results of a new long-term followup study where we measured ADP-induced platelet-fibrin
clot strength (MAADP) by the TEG Platelet Mapping assay
in addition to MATHROMBIN and LTAADP and compared
their association with post-PCI ischemic event occurrence with the aim of future use of these tests to
personalize antiplatelet therapy.
Methods
Patients
The study was approved by the Investigational Review Board
of Sinai Hospital, Baltimore, MD. Two hundred twenty-five
consecutive patients undergoing nonemergent PCI were prospectively enrolled between 2004 and 2005 after providing
informed consent. All patients were older than 18 years.
Inclusion and exclusion criteria were described previously.5
Aspirin (325 mg) was administered to all patients on the day of
the procedure and daily thereafter (81-325 mg). Sixty-six
percent of the patients received a 300-mg (n = 73) or 600-mg
(n = 75) clopidogrel loading dose immediately after successful
PCI, with a 75-mg/d maintenance dose thereafter. Patients on a
maintenance dose of clopidogrel (75 mg/d) at the time of
admission (n = 77) did not receive a loading dose. Eptifibatide
was administered to 123 patients. Unfractionated heparin was
administered to all patients during the procedure to achieve a
clotting time of 200 to 250 seconds for patients administered a
GPIIb/IIIa inhibitor and N300 seconds for all other patients.
Blood samples were obtained at 18 to 24 hours post-PCI; an
additional sample was collected 5 days post-PCI in patients
treated with eptifibatide. In those patients not treated with
eptifibatide, measurements from the 18- to 24-hour sample
were correlated with clinical outcomes, whereas in those
patients treated with eptifibatide, the measurements from day
5 were used in the analysis. In patients experiencing bleeding,
an additional blood sample was obtained at or close to the
time of the bleeding event. We collected three 5-mL
Vacutainer tubes (Beckton-Dickenson, Franklin Lakes, NJ), 2
containing 3.2% trisodium citrate for light transmittance
aggregometry and 1 containing 40 USP lithium heparin for
TEG Platelet Mapping analysis.
Platelet-fibrin clot strength measurement
Platelet-fibrin clot strength measurements were carried out
using the TEG Hemostasis System (Haemoscope Corporation,
Niles, IL). The TEG Hemostasis Analyzer with automated
analytical software provides quantitative and qualitative measurements of the physical properties of a clot.5
The TEG technology is described elsewhere.5,6 Briefly, a
stationary pin is suspended into an oscillating cup that contains
the whole blood sample. As the blood clots, it links the pin to the
Gurbel et al 347
cup. Clot strength is determined by measuring the amplitude of
the rotation of the pin, which increases proportionally with clot
strength. Maximum amplitude represents maximum clot
strength, expressed as the MA parameter.5,6
Light transmittance aggregation
Platelets in platelet-rich plasma were stimulated with 5 μmol/
L ADP and 2 mmol/L arachidonic acid (AA) (Chronolog,
Havertown, PA). Aggregation was assessed using a Chronolog
Lumi-Aggregometer (Model 490-4D) with the Aggrolink software package. Aggregation was expressed as the maximum
percentage change in light transmittance, using platelet poor
plasma (PPP) as a reference.5,6
Clinical end points
Patients were followed for the occurrence of adverse events
during index hospitalization and for up to 36 months. Patients
were contacted either by phone or by office appointment to
determine event occurrence and compliance with antiplatelet
drug therapy. The primary end point was the composite of
cardiac death, stent thrombosis, myocardial infarction, ischemic
stroke, and unplanned revascularization. First events are
reported. Cardiac death was defined as death secondary to
any cardiovascular cause. Myocardial infarction was defined as
the occurrence of symptoms of myocardial ischemia associated
with troponin I values greater than the upper limits of normal.7
Stent thrombosis was defined as definite stent thrombosis
according to the Academic Research Consortium.8 The secondary end point was the composite of major and minor bleeding
during the observation period. Bleeding was quantified according to the Thrombolysis in Myocardial Infarction criteria.9 Two
independent physicians blinded to laboratory data adjudicated
events after review of source documents.
Statistical analysis
Categorical variables are expressed as number (percentage) and
continuous variables as mean ± SD, with P b .05 considered
statistically significant. The Fischer exact test and Mann-Whitney
rank sum test were used for comparison of categorical variables,
and Student t test was used for comparison of continuous
variables between groups. Receiver operating characteristic curve
(ROC) analysis (MedCalc software, Mariakerke, Belgium) was
performed to identify the best discriminatory level of MATHROMBIN, MAADP, and LTAADP associated with first ischemic
events. The predictive values of the 3 measurements were
assessed by ROC comparison analysis. To assess event-free
survival, a Kaplan-Meier analysis was performed; and the eventtime data are reported in 2 curves according to the cut point of
each platelet function parameter determined by ROC analysis.
Univariate comparisons between patients with and without
ischemic events were performed using the χ2 test, Mann-Whitney
U test, or Student t test as appropriate. Demographic and
procedural variables with P values b.1 in the univariate analysis
were entered by stepwise forward selection in a multivariate Cox
proportional hazards model (SAS software, Cary, NC).
Sample size calculation
A recent study demonstrated that ∼20% of patients undergoing PCI will experience death or repeated revascularization
within 3 years; and it has been demonstrated that patients with
American Heart Journal
August 2010
348 Gurbel et al
Table I. Patient characteristics
Age, y
Gender and ethnicity, n (%)
White male
White female
African American male
African American female
BMI, kg/m2
Systolic BP, mm Hg
Diastolic BP, mm Hg
Presentation, n (%)
Elective
Unstable angina
Myocardial infarction
Risk factors/past medical history, n (%)
Smoking
Family history of CAD
Hypertension
Hyperlipidemia
Diabetes
Peripheral vascular disease
Prior myocardial infarction
Prior CABG
Prior PTCA
Prior CVA
Baseline medications, n (%)
β-Blockers
ACE inhibitors
Calcium-channel blockers
Lipid-lowering agents
PPI
Laboratory data
WBC, ×1000/mm3
Platelets, ×1000/mm3
Hemoglobin, g/dL
Hematocrit, %
Creatinine, g/dL
Total group (N = 225)
Ischemic group (n = 59)
Nonischemic group (n = 166)
P
66 ± 12
66 ± 12
64 ± 11
.24
121 (54)
44 (20)
30 (13)
30 (13)
29 ± 7
144 ± 25
75 ± 17
30 (48)
14 (22)
8 (13)
7 (11)
30 ± 6
144 ± 21
75 ± 16
91 (55)
30 (18)
22 (13)
23 (14)
29 ± 7
146 ± 24
76 ± 17
.18
.25
1.0
.28
.30
.57
.69
159 (71)
50 (22)
16 (7)
44 (75)
12 (20)
3 (5)
115 (69)
38 (22)
13 (8)
.19
.37
.22
124 (55)
106 (48)
167 (74)
179 (80)
87 (41)
19 (8)
75 (33)
54 (24)
79 (35)
27 (12)
31 (52)
31 (52)
47 (79)
52 (89)
33 (56)
6 (10)
22 (37)
14 (23)
27 (47)
5 (9)
93 (56)
75 (47)
118 (72)
127 (77)
60 (36)
13 (8)
53 (32)
40 (24)
52 (31)
22 (13)
.29
.25
.25
.02
.004
.32
.24
.44
.01
.21
190 (84)
146 (65)
59 (26)
184 (82)
76 (34)
49
38
23
50
21
141 (85)
108 (65)
36 (22)
134 (81)
55 (33)
.36
1.0
.005
.45
.34
7.5 ± 2.4
228 ± 70
13.5 ± 2.1
40.1 ± 5.3
1.1 ± 0.6
.12
.29
.10
.37
1.0
7.8 ± 3.0
231 ± 71
13.4 ± 2.0
39.9 ± 5.2
1.1 ± 0.5
(83)
(65)
(39)
(85)
(36)
8.6 ± 3.8
239 ± 69
13.0 ± 1.9
39.4 ± 5.0
1.1 ± 0.5
BMI, Body mass index; BP, blood pressure; CAD, coronary artery disease; CABG, coronary artery bypass graft surgery; CVA, cerebrovascular accident; ACE, angiotensin-converting
enzyme; PPI, proton pump inhibitors; WBC, white blood cells.
high platelet reactivity have greater event frequency, with
adjusted hazard ratios reported to be at least 3.0.10,11 We
hypothesized an ∼25% incidence of ischemic events in patients
with high platelet reactivity as compared with 10% incidence in
patients with normal platelet reactivity. Using the sample size
calculation from SigmaStat software (Systat Software, Inc, San
Jose, CA), it was estimated that the sample size required for 90%
power with the α of 0.05 and a 5% dropout was ∼225 patients.
The authors had full access to and take full responsibility for
the integrity of the data. All authors have read and agree to the
manuscript as written.
Results
Demographic and procedural characteristics
Two hundred twenty-five patients undergoing PCI
were enrolled. Fifty-nine patients (26%) sustained an
ischemic event within 3 years after the index PCI. Patient
demographics and procedural characteristics are shown
in Tables I and II, respectively. Briefly, patients with
ischemic events had a higher prevalence of hyperlipid-
emia, diabetes, prior percutaneous transluminal coronary
angioplasty (PTCA), and calcium-channel blocker use and
had lower ejection fraction as compared with patients
without ischemic event. Patients within the ischemic
group had more complex disease, smaller vessel diameter, and more implanted stents.
Ischemic event occurrence
Two percent of patients had an ischemic event within 1
month of PCI, and 26% experienced an ischemic event
within the 3 years after the index PCI (Table III). Twentyfour percent of patients (14/59) had their event after
clopidogrel discontinuation with a mean duration of
therapy of 6.4 ± 3 months. Ninety-eight percent of
ischemic events occurred during aspirin treatment.
Association between platelet function parameters and
adverse ischemic events
In patients experiencing an ischemic event, measures
of thrombin-induced and ADP-induced platelet-fibrin
American Heart Journal
Volume 160, Number 2
Gurbel et al 349
Table II. Procedural characteristics
Table III. First ischemic events
Total
Ischemic Nonischemic
group
group
group
(N = 225) (n = 59)
(n = 166)
Total group (N = 225)
P
Month <1
Length of
60 ± 32
procedure, min
Ejection fraction, %
53 ± 38
No. of vessels treated
1.3 ± 0.6
Culprit lesion
morphology, n (%)
De novo
200 (88)
Restenotic
25 (12)
22 (10)
Bifurcation lesion,
severe calcification,
evidence of
thrombus,
or total occlusion
ACC/AHA lesion
score, n (%)
Type A
19 (8)
Type B1
65 (29)
Type B2
51 (23)
Type C
90 (40)
Culprit lesion
location, n (%)
LAD
77 (34)
CX
56 (25)
RCA
80 (36)
SVG
12 (5)
Stent types, n (%)
Drug eluting
169 (75)
Bare metal
51 (23)
PTCA only
9 (4)
Reference vessel
3.0 ± 0.05
diameter, mm
Total lesion
22 ± 14
length, mm
Predilation, n (%)
121 (54)
Postdilation, n (%)
109(48)
Total stents per
1.5 ± 1.0
patient, n
Procedural
219
success, n (%)
56 ± 27
59 ± 33
.52
49 ± 11
1.4 ± 0.6
55 ± 15
1.3 ± 0.5
.005
.21
50 (85)
9 (15)
10 (17)
150 (90)
16 (10)
12 (7)
.15
.15
.01
4
13
13
29
(7)
(22)
(22)
(49)
15 (9)
52 (31)
38 (23)
61 (37)
.32
.10
.44
.05
19
11
26
3
(32)
(19)
(44)
(5)
58
45
54
9
.34
.11
.05
.39
Ischemic events, n (%)
Cardiac death
Stent thrombosis
Myocardial infarction
Target vessel revascularization
Nontarget vessel
revascularization
Total ischemic events, n (%)
1
4
0
0
0
(0.4)
(1.7)
(0.0)
(0.0)
(0.0)
5 (2.2)
Month
1-36
0
2
17
26
9
Month
0-36
(0.0)
(0.8)
(7.5)
(11.6)
(4.0)
1 (0.4)
6 (2.5)
17 (7.5)
26 (11.6)
9 (4.0)
54 (24.0)
59 (26.2)
Table IV. Platelet function parameters
(35)
(27)
(32)
(6)
49 (78)
11 (25)
3 (5)
2.9 ± 0.4
120 (72)
40 (24)
6 (4)
3.1 ± 0.5
.19
.44
.37
.005
21 ± 9
22 ± 16
.64
30 (51)
32 (54)
1.7 ± 1.2
91 (55)
77 (46)
1.4 ± 0.8
.29
.15
.03
58 (98)
161 (97)
.34
ACC/AHA, American College of Cardiology/American Heart Association; LAD, left
anterior descending artery; CX, circumflex artery; RCA, right coronary artery; SVG,
saphenous vein graft.
clot strength (MATHROMBIN and MAADP, respectively)
were significantly higher than in patients free from
ischemic events (Table IV). In contrast, AA-induced
platelet-fibrin clot strength (MAAA) was highly inhibited
in both groups. The association of platelet function
parameters and ischemic events was assessed with ROC
analysis as shown in Figure 1. In comparison with
LTAADP and MATHROMBIN, MAADP had the best predictive
value yielding an area under the curve of 0.84 (95% CI
0.78-0.89, P b .001 for all comparisons).
In univariate Cox proportional hazard model analysis
using the ROC cut point, MATHROMBIN, LTAADP, and
MAADP were associated with a 3.8-fold (95% CI 2.1-7.0),
4.8-fold (95% CI 2.4-9.6), and 10.3-fold (95% CI 5.4-20.0)
TEG
MATHROMBIN, mm
MAADP, mm
MAAA, mm
LTA
LTAADP
Ischemic
group
Nonischemic
group
P
72 ± 6
51 ± 12
18 ± 10
67 ± 6
35 ± 13
15 ± 10
b.0001
b.0001
.04
45 ± 13
31 ± 15.
b.0001
relative risk of ischemic event occurrence, respectively
(P b .0001 for each). The occurrence of cardiac events
over time is depicted in Kaplan-Meier event-time curves
(Figure 2) and demonstrate the association of events to
platelet function parameters by cut point (MAADP N47
and ≤47 mm, MATHROMBIN N69 and ≤69 mm, and
LTAADP N34% and ≤34%). The separation of the 2
curves occurred early, particularly for MAADP. Patients
with high platelet function values had a continual
increase in ischemic event occurrence over time. In a
multivariate Cox proportional hazards model used to
identify independent predictors of long-term ischemic
events, platelet function parameters (MATHROMBIN, LTAADP, and MAADP) as well as patient and procedural
characteristics with a P b .10 in the univariate analysis
were examined (Tables I and II). When adjusted for
patient and procedural covariates, MAADP was independently and significantly associated with adverse ischemic events, with a hazard ratio of 10.9 (95% CI 5.6-21.3)
(Table V). With the exception of MATHROMBIN and
calcium-channel blockers, all other variables were
excluded from the model when MAADP was the platelet
function parameter studied.
Quartile analysis of the platelet function parameters
consistently showed low incidence of ischemic events
in the lower quartiles with increasing incidence of
ischemic events in higher quartiles of MATHROMBIN,
MAADP, and LTAADP (Figure 3). In the fourth quartile of
American Heart Journal
August 2010
350 Gurbel et al
Figure 1
Comparison of ROC curves for MATHROMBIN, MAADP, and LTAADP. AUC, Area under the curve. PPV, positive predictive value; NPV, negative
predictive value. ⁎P b .0001.
MATHROMBIN (MATHROMBIN N72), 43% had ischemic
events (Figure 3). Of patients without an ischemic
event in the highest MATHROMBIN quartile, 86% had an
MAADP equal to or less than the cut point of 47 mm. In
contrast, 81% of patients with an ischemic event had an
MAADP above this cut point (Figure 4).
Bleeding events
Fifteen patients experienced a bleeding event; 5
patients had major bleeding and 10 patients had minor
bleeding. Eight of the bleeding events occurred during
the index hospitalization, and 6 of these patients received
a GPIIb/IIIa inhibitor. Four patients had a bleeding event
within 30 days after discharge, and the remaining 3
patients experienced bleeding between 30 days and 3
years of follow-up. In those patients not on GPIIb/IIIa
inhibitors, there was no difference in any platelet
function parameters (data not shown).
Of the 6 patients treated with a GPIIb/IIIa inhibitor
who had a major bleeding event, all had an MAADP value
within the first quartile at the time of the bleed. Those
patients receiving the same GPIIb/IIIa inhibitor treatment (n = 115) who had an MAADP value beyond the first
quartile did not bleed. This indicates that the strength of
the clot as measured by MAADP, and not the mere
presence of a GPIIb/IIIa inhibitor, determines the
probability of patient bleeding.
Although the low number of bleeding patients
precludes definitive statistical analysis, nevertheless,
the data trends warrant consideration. As expected,
MAADP measured at or close to the time of the bleed
was low, with 83% falling within the first quartile of
MAADP. Notably, in the case of major bleeding, all
instances fell within the first quartile. In addition, ROC
curve analysis for bleeding produced a cut point of 31,
which approximates the upper limit of the first quartile
(Figure 3).
Discussion
Thrombus formation is a dynamic and nonlinear
process involving many interacting elements, most
notably the vascular wall, blood components, and blood
flow. Light transmittance aggregometry has long been the
methodology of choice to determine platelet reactivity.
However, our study suggests that the TEG MA parameters, MAADP and MATHROMBIN, provide additional
information for post-PCI risk assessment. In vivo, the
strength of the clot determines whether it will resist the
American Heart Journal
Volume 160, Number 2
Figure 2
Gurbel et al 351
Table V. Cox proportional hazards regression
Covariate
MAADP N47 mm
MATHROMBIN N69 mm
Calcium-channel blockers
LTAADP N34%
Hx of prior PTCA
Calcium-channel blockers
Adjusted HR (95% CI)
10.9
3.5
2.3
5.6
2.1
2.2
(5.6-21.3)
(1.9-6.4)
(1.2-4.1)
(2.7-11.6)
(1.2-3.7)
(1.2-4.3)
P
b.0001
b.0001
.008
b.0001
.01
.016
Each cluster represents analysis of each of the platelet function parameters and
covariates (only variables retained by the analysis are shown). HR, Hazard ratio;
Hx, history.
Cumulative incidence of first ischemic events (Kaplan-Meier) during
3-year follow-up period for platelet function parameters.
shear forces of the circulating blood or impede blood
flow and result in an ischemic event. The TEG MA
parameters measure the strength of a clot as a direct
function of the maximum dynamic properties of fibrinplatelet binding via GPIIb/IIIa and the platelet contractile
system (secondary aggregation). Therefore, the TEG MA
parameters may better estimate the in vivo situation as
compared with LTA, which measures platelet aggregation
mediated by fibrinogen (primary aggregation) and
ignores the important contribution of platelet-fibrin
interactions to both thrombosis and hemorrhage.
The existence of a high level of individual variability in
platelet responsiveness to antiplatelet therapy and ontreatment platelet reactivity has been confirmed in most
clinical studies examining antiplatelet therapy efficacy in
PCI patients.3 Interindividual variability has also been
demonstrated in thrombin-generating ability of blood.12
It is widely accepted that ischemic events, particularly
post-PCI, are multifactorial processes influenced by
clinical, demographic, procedural, and hemostatic components that culminate in a thrombotic expression, that
is, an ischemic event. This study collected information
on many of the accepted risk factors and examined in
particular several of the hemostatic components that
contribute to and quantify the subjects' prothrombotic
state. We were able to identify a set of hemostasis
markers by TEG and LTA that were able to risk stratify
patients for ischemic events both independently and
together. In contrast, we found that few of the standard
risk indicators were significantly different between
patients with and without ischemic events and were
eliminated in multivariate Cox proportional hazards
model analysis in the presence of platelet function
measurements. These results indicate that in predicting
ischemic events, the incremental contributions of most
other variables besides MAADP, MATHROMBIN, and LTAADP
are statistically not significant. This was not unexpected
because standard risk factors may predispose a patient
for an ischemic event, but it is the patient's hemostasis
state that will ultimately determine whether the forming
clot can resist the shear forces of the circulating blood
and cause the event.
We showed in the PREPARE POST-STENTING study
that MATHROMBIN and LTAADP identified patients at high
American Heart Journal
August 2010
352 Gurbel et al
Figure 3
Figure 4
Fourth quartile of MATHROMBIN showing MATHROMBIN with corresponding MAADP value for each patient. Left portion displays patients
with repeated ischemic events; and right portion, without ischemic
events. Dotted lines indicate cut points for ischemic and bleeding risk,
and delineate a possible therapeutic range.
Quartile distribution of ischemic events for each platelet function
parameter.
risk for 6-month post-PCI ischemic event occurrence.5
High MATHROMBIN (N72 mm) alone was highly predictive
of a recurrent ischemic event. In a study of patients
undergoing a variety of noncardiac surgical procedures,
MATHROMBIN was also highly predictive of postoperative
ischemic events.13 In our current study of 3-year
ischemic event occurrence, MAADP, MATHROMBIN, and
LTAADP were all associated with high negative predictive
values, with MAADP having the highest specificity (85%)
(Figure 1).
In the absence of platelet inhibitors, platelets
circulating in the vascular system function at maximum
potential in any given patient. Maximal platelet
reactivity is measured by MATHROMBIN. However, in
the presence of platelet inhibitors, circulating platelets
are variably inhibited. The MAADP and MAAA indicate
the level of platelet reactivity to ADP and COX-1
activity, respectively. The quartile analysis of both
MATHROMBIN and MAADP (Figure 3) indicates that
patients falling into higher quartiles may require more
aggressive antiplatelet therapy to prevent ischemic
events because the incidence of ischemic events
increases in each quartile.
Our results indicate that in the presence of platelet ADP
inhibition, MAADP is a strong predictor of long-term postPCI ischemic events regardless of how high the level of
MATHROMBIN may be (Figure 4), suggesting its potential
superiority over LTAADP and MATHROMBIN as a risk
assessment tool. The latter also suggests its potential
utility to determine individualized therapy. Eighty-seven
percent of ischemic events occurred in the third and
fourth quartiles of MAADP (Figure 3), which correlates
well with the ROC cut point. Consequently, we propose
the MAADP cut point (47 mm) as the upper limit of a
therapeutic target for this population. A lower limit of
MAADP to define a potential therapeutic window will
require a much larger study, although the presence of
bleeding in the lowest quartile and the absence of
bleeding in higher quartiles suggest a lower therapeutic
limit of approximately 30 mm, which delimits the first
quartile of MAADP and corresponds to the ROC cut point
for the MAADP taken at the time of the bleed (Figure 4).
Thus, for the first time, using the bleeding cut point of 31
and the ischemic cut point of 47, a therapeutic range of
31 to 47 for MAADP can be proposed, providing maximum
efficacy and safety. This is in contrast to the results of the
prospective POPULAR study that demonstrated that the
American Heart Journal
Volume 160, Number 2
LTA, VerifyNow P2Y12, and Plateletworks platelet
function tests were also able to identify patients at higher
risk for ischemic events; but none of the tests was able to
identify patients at risk for Thrombolysis in Myocardial
Infarction major and minor bleeding.14
MATHROMBIN reflects the patient's maximal potential
platelet reactivity, and MAADP reflects platelet reactivity
to ADP and assesses the individual patient's response to
antiplatelet therapy. MAADP is partially determined by
MATHROMBIN because MATHROMBIN represents the upper
boundary of platelet reactivity. Therefore, if MATHROMBIN
is low or normal, MAADP must also be low or normal.
Thus, when MATHROMBIN is low or normal, the administration of a potent P2Y12 inhibitor may enhance
bleeding risk. On the other hand, if MATHROMBIN is
high, given the wide response variability to clopidogrel,
MAADP may be high, normal, or low. The analysis of
patients in the fourth quartile of MATHROMBIN with
respect to MAADP suggests the important role of platelet
reactivity to ADP in determining ischemic event
occurrence in these patients (Figure 4).
With this in mind, when considering the American
College of Cardiology/American Heart Association PCI
guidelines for dosing and duration of poststenting
antiplatelet therapy, 2 areas of concern arise. First, the
notion that a “one size fits all” dosing of antiplatelet drugs
is the appropriate treatment for a given PCI patient is
flawed. The interindividual variability in on-treatment
platelet reactivity during clopidogrel treatment confirmed by multiple prior studies predominantly using
LTA is now confirmed by another measurement, MAADP.
Second, the implication of the guidelines is that
hemostasis is “time dependent” and that discontinuing
therapy based on a fixed elapsed time after intervention is
inappropriate. Our results demonstrate that a range of
maximal platelet-fibrin clot strength exists and that 50%
of patients (2 highest quartiles for MATHROMBIN) are at
high risk for poststenting ischemic events. Thus, when
P2Y12 blocking therapy is discontinued in this group, a
high event rate would also be expected (Figure 3)
(MATHROMBIN quartiles). Therefore, our data suggest that
investigations designed to assess the safety of P2Y12
inhibitor therapy cessation should also focus on an
individual assessment of hemostasis rather than only a
uniform elapsed time interval postintervention. A measurement of native maximal platelet function such as
MATHROMBIN, which is uninfluenced by ongoing antiplatelet therapy, is needed for future studies of risk assessment
to determine if and when a patient may be safely taken off
antiplatelet therapy after stenting.
Limitations
This was an observational study. A prospective study in
which patients are treated according to the TEG results is
needed to confirm that personalized management of
Gurbel et al 353
platelet reactivity with antiplatelet drugs is more effective
than conventional therapy in reducing the incidence of
ischemic events and bleeding.
Conclusions
Management of patients using universal fixed-dosing
dual-antiplatelet therapy is associated with an unacceptable rate of recurrent events. This study was able to
characterize post-PCI patients according to risk for longterm recurrence of ischemic events based on selected
TEG Platelet Mapping results, specifically MAADP and
MATHROMBIN. This is the first study to compare the
prognostic utility of conventional aggregometry with TEG
for long-term events and also the first to examine the role
of MAADP as a prognostic tool. Thrombelastography
measures secondary aggregation, whereas all other
point-of-care tests and LTA measure primary aggregation,
ignoring the contribution of fibrin and platelet contractility in the method. This may explain the increased ability
of the TEG to risk stratify. An assessment of platelet-fibrin
interactions by TEG, particularly by measurement of
MAADP, may facilitate future investigations of personalized antiplatelet treatment designed to reduce poststenting ischemic events, manage bleeding risk, and determine
appropriate cessation of therapy.
Sources of funding
The study was supported by Sinai Hospital of Baltimore
and National Institutes of Health grant R44-HL059753.
Disclosures
Paul A. Gurbel has received research funding from Astra
Zeneca, Daiichi Sankyo, Lilly, Schering-Plough, Pozen,
Portola Pharmaceuticals, Bayer Healthcare, Sanofi-Aventis, Haemonetics, and NIH. Eli Cohen and Irene Navickas
are former employees of Haemoscope Corporation. All
other authors report no conflicts of interest.
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